It is well known that our cells produce, from their DNA, messenger RNAs (mRNAs) and corresponding proteins, many of which are known while many are not yet known, and by which biologic activities are regulated. By studying such mRNAs and constructing corresponding cDNAs (complementary cDNAs), it is possible to find new molecules and new utilities to regulate cell biologic activities and modify their pathologic alterations.
Programmed cell death, or apoptosis (ref. 1), is a fundamental process in the regulation of many biologic processes. Indeed, either in differentiation processes and in mature tissues, balance between cellular compartments is determined by the ratio between cellular proliferation and programmed cell death. Alterations, either as a deregulated stimulation or a defective functioning, of apoptosis underlie many pathologies. Tissue degenerative diseases (of brain, such as in several forms of dementia, and of various other tissues) or diseases due to tissue acute damages (like infarcts of hearth, brain or other organs) or to excessive and/or deregulated inflammation involve apoptosis. Finding elements and tools that regulate apoptosis is important since it can allow, in these cases, to block the death process that causes the disease. On the other hand, in other pathologies, such as autoimmune diseases, apoptosis deregulation leads to aberrant expansion of cells, that attack our organism. Elements able to regulate apoptosis can, in these cases, equilibrate the death process in these cells and cure the disease. In other pathologies, including first of all neoplasias, cells display a reduced sensitivity to apoptosis and this leads to two consequences: one in pathogenesis, since the reduced sensitivity to apoptosis underlies the neoplastic clone expansion, and the other in therapy, since such reduced sensitivity determines neoplastic cell resistance to therapies (chemo- and radiotherapies, therapies with biological modifiers, etc.) that should induce their death. Finding elements that regulate apoptosis can therefore allow to either fight the arising of neoplasia and determine therapeutically neoplastic cell death. This indeed today represents a fundamental approach of research in oncology. Finally, in other conditions like ageing, or in hyperplastic or dysplastic alterations like myelodisplastic diseases and others, apoptosis exerts a fundamental role and to be able to affect it can allow to affect the process.
Several apoptosis-regulating elements are known: caspases, intracellular enzymes that can induce cell death, and their inhibitors or activators; proteins of mitochondrion, an organelle in which fundamental apoptosis-regulating processes take place; and other molecules. However, evidence in literature indicate that there are other elements, not yet characterised, that regulate apoptosis (1). For example, apoptosis can be regulated by the activity of transcription factors NF-κB/Rel (Ref. 6). However, it is still poorly known what are all genes on which these transcription factors act in regulating apoptosis. We therefore aimed at identifying, through modulating NF-κB/Rel activity, novel nucleotide sequences able to affect apoptosis.